Method of treatment using bisphosphonic acid

ABSTRACT

The present invention refers to a pharmaceutical composition of a bisphosphonic acid or salt thereof, and an excipient thereof, and a method of treating disorder characterized by pathologically increased bone resorption comprising orally administering at least 150% of the expected efficious daily dose of a bisphosphonic acid or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients thereof and administering the dose at a period of one two or three consecutive days per month.

PRIORITY TO RELATED APPLICATIONS

This application is a Continuation of Ser. No. 10/430,007, filed May 6,2003, which is now pending.

FIELD OF THE INVENTION

The present invention refers to the use of bisphosphonic acids,especially of(1-hydroxy-3-(N-methyl-N-pentyl)aminopropylidene-1,1-bisphosphonic acid(ibandronic acid) or pharmaceutically acceptable salts thereof for themanufacture of pharmaceutical compositions for the prevention or thetreatment of disorders characterized by pathologically increased boneresorption, especially for the prevention and treatment of osteoporosis.

BACKGROUND OF THE INVENTION

Bones serve mainly as a support, and consequently bone is frequentlyregarded as a simple building material. However, bone is a complicatedbiomaterial adapted to a wide variety of requirements, stimuli and noxaeto which it is exposed. Endoprostheses are available as substitutes forbones and joints. However, endoprostheses, even when biomechanicallyhighly refined, do not have an active effect on the environmental andload factors.

A variety of disorders in humans and mammals involve or are associatedwith abnormal bone resorption. Such disorders include, but are notlimited to, osteoporosis, Paget's disease, periprosthetic bone loss orosteolysis, and hypercalcemia of malignancy and metastatic bone disease.The most common of these disorders is osteoporosis, which in its mostfrequent manifestation occurs in postmenopausal women. Becauseosteoporosis, as well as other disorders associated with bone loss, arechronic conditions, it is believed that appropriate therapy willgenerally require chronic treatment.

Bisphosphonates, i.e. bisphosphonic acids or pharmaceutically acceptablesalts thereof, are synthetic analogs of the naturally occurringpyrophosphate. Due to their marked affinity for solid-phase calciumphosphate, bisphosphonates bind strongly to bone mineral.Pharmacologically active bisphosphonates are well known in the art andare potent inhibitors of bone resorption and are therefore useful in thetreatment and prevention of diseases involving abnormal bone resorption,especially osteoporosis, Paget's disease, hypercalcemia of malignancy,and metastatic and metabolic bone diseases.

Bisphosphonates as pharmaceutical agents are described for example inEP-A-170,228; EP-A-197,478; EP-A-22,751; EP-A-252,504; EP-A-252,505;EP-A-258,618; EP-A-350,002; EP-A-273,190; and WO-A-90/00798, each ofwhich are incorporated herein by reference.

Pharmaceutical forms of currently marketed bisphosphonates are oralformulations (tablets or capsules) or solutions for intravenousinjection or infusion. They are systemically well tolerated whenadministered at therapeutic doses. However, bisphosphonates as a classare irritant to skin and mucous membranes and when given orally on acontinuous basis may result in digestive tract side effects, e.g.,esophageal adverse events or gastrointestinal disturbances. As aconsequence, and due to their low oral bioavailability, the oral routeof administration has, to date, had to follow inconvenientrecommendations of use for the patient.

Bisphosphonates can be classified into two groups with different modesof action. Ibandronate belongs to the more potent nitrogen-containingbisphosphonates[Russell 1999 Russell R G G, Rogers M J. Bisphosphonates:From the laboratory to the clinic and back again. Bone 25(1):97–106(1999); Rogers M J, Gordon S, Benford H L, Coxon F P, Luckman S P,Monkkonen J, Frith J C. Cellular Molecular mechanisms of action ofbisphosphonates. Cancer 88 (12) Suppl:2961–2978 (2000)]. Ibandronate isone of the most potent bisphosphonates currently under clinicaldevelopment in osteoporosis and metastatic bone diseases. In animalmodels of bone resorption, ibandronate is 2, 10, 50 and 500 times morepotent than risedronate, alendronate, pamidronate, and clodronaterespectively[Mühlbauer R. C., F. Bauss, R. Schenk, M. Janner, E. Bosies,K. Strein, and H. Fleisch. BM 21.0955 a potent new bisphosphonate toinhibit bone resorption. J. Bone Miner. Res. 6: 1003–1011 (1991)].

Ibandronate inhibits bone resorption without any impairment ofmineralization (Mühlbauer et al Mühlbauer R. C., F. Bauss, R. Schenk, M.Janner, E. Bosies, K. Strein, and H. Fleisch. BM 21.0955 a potent newbisphosphonate to inhibit bone resorption. J. Bone Miner. Res. 6:1003–1011 (1991).). It has been shown to decrease osteoclastic activity,thus inhibiting bone destruction. At high doses it also reduces thenumber of osteoclasts (Mühlbauer et al. Mühlbauer R. C., F. Bauss, R.Schenk, M. Janner, E. Bosies, K. Strein, and H. Fleisch. BM 21.0955 apotent new bisphosphonate to inhibit bone resorption. J. Bone Miner.Res. 6: 1003–1011 (1991)).

As described, bisphosphonates are accepted as providing strong efficacyin the management of osteoporosis. However, given the administrationrestrictions related to low oral bioavailability and potential forgastro-intestinal effects, there is a clear opportunity for regimenswhich offer improved convenience and flexibility, leading to a higherlevel of compliance and superior patient management/satisfaction.Intermitted regimens such as, for example, once weekly administrationhave been described in the art.

SUMMARY OF THE INVENTION

It has now been found that the prevention or the treatment of disorderscharacterized by pathologically increased bone resorption such asosteoporosis, can be improved by a monthly administration of 50 to 250mg of a bisphosphonate or pharmaceutical acceptable salt thereof,especially by a monthly administration of ibandronate, i.e., ibandronicacid or a pharmaceutically acceptable salt thereof.

The present invention is thus concerned with the use of a bisphosphonicacid or a pharmaceutical acceptable salt thereof, especially with theuse of ibandronic acid or a pharmaceutical acceptable salt thereof, forthe preparation of pharmaceutical compositions for the prevention or thetreatment of disorders characterized by pathologically increased boneresorption, wherein the medicament comprises about 50 to 250 mg,preferably about 100 to 150 mg, of a bisphosphonic acid or a acceptablesalt thereof; and orally administered in a period of one, two or threeconsecutive days per month.

Monthly oral treatment by administration of at least 120%, especially of120% to 200%, of the expected efficacious daily dose offers incrementalpatient benefits with respect to convenience and compliance as well assuperior results. Prior to the completion of the ibandronate clinicaldevelopment program, no bisphosphonate had prospectively demonstratedfracture reduction efficacy with a drug-free interval beyond dailyadministration. In summary, it is quite unexpected that fracturereduction benefit can be derived from a monthly administration of anoral bisphosphonate with a single or multiple tablet administrationscheme.

Accordingly, the present invention relates to the use of bisphosphonicacids or pharmaceutically acceptable salts, especially ibandronic acidor pharmaceutically acceptable salts thereof for the manufacture of amedicament for the prevention or treatment of disorders characterized bypathologically increased bone resorption, e.g. osteoporosis, wherein themedicament comprises at least 120% of the expected efficacious dailydose of a bisphosphonic acids or acceptable salts thereof and isadministered on one, two or three consecutive days per month.

More preferably the invention comprises the use of ibandronic acid orpharmaceutically acceptable salts thereof for the manufacture of amedicament for the prevention or the treatment of disorderscharacterized by pathologically increased bone resorption wherein themedicament

-   a) comprises about 100 to about 150 mg of ibandronic acid or a    pharmaceutically acceptable salt thereof and-   b) is orally administered in a period of one, two or three    consecutive days per month.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The term “bisphosphonic acid” means compounds characterized by twophosphonate groups linked by phosphoether bonds to a central (geminal)carbon atom. Such a P—C—P structure is represented by compound I (see,page 6). The use of a specific nomenclature in referring to thebisphosphonate or bisphosphonates is not meant to limit the scope of thepresent invention, unless specifically indicated.

The term “pharmaceutically acceptable” as used herein means that thesalts or chelating agents are acceptable from a toxicity viewpoint.

The term “pharmaceutically acceptable salt” refers to ammonium salts,alkali metal salts such as potassium and sodium (including mono, di- andtri-sodium) salts (which are preferred), alkaline earth metal salts suchas calcium and magnesium salts, salts with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such as arginine, lysine, and so forth.

The term “disorders characterized by pathologically increased boneresorption” refers to medically defined conditions with or withoutidentifiable cause (such as post-menopausal osteoporosis, idiopathicjuvenile osteoporosis, Klinefelter's syndrome; male osteoporosis;osteoporosis due to nutritional factors; organ transplant relatedosteoporosis; immobilization associated osteoporosis; inflammatorycondition and cortico-steroid induced osteoporosis).

The term “one, two or three consecutive days per month” meansadministration of one to three dose proportional or non-doseproportional tablets on one, two or three consecutive days of the month,preferably on one day per month. As used herein, the term “month” isused in accordance with the generally accepted meaning as a measure oftime amounting to approximately four (4) weeks, approximately 30 days,or approximately 1/12 Of a calendar year.

The term “medicament” refers to a pharmaceutical composition. The termencompasses single or multiple administration schemes.

Preferably, the medicament is administered on one day per month.Preferably, the medicament is administered as a single dose, however,the scope of the present invention includes pharmaceutical compositionsadministered as multiple sub-doses such as on two consecutive day permonth or on three consecutive days per month.

Preferably, the medicament comprises at least 100%, preferably 120% to200% of the efficacious dose of bisphosphonic acids or pharmaceuticallyacceptable salts thereof, more preferably of ibandronic acid orpharmaceutically acceptable salts thereof.

The term “efficacious dose” refers to about 50 to about 250 mg, morepreferably to about 100 to about 150 mg, of a bisphosphonate or apharmaceutically acceptable salt thereof, for example, of ibandronicacid or a pharmaceutically acceptable salt thereof. As noted, theefficacious dose may be a single dose or multiple sub-doses. Forexample, if the efficacious dose is 150 mg, the dose may be one (1) 150mg dose, two (2) 75 mg sub-doses administered on one day or on twoconsecutive days, or three (3) 50 mg sub-doses administered on one dayor on two or three consecutive days; if the efficacious dose is 100 mg,the dose may include one (1) 100 mg dose, two (2) 50 mg sub-dosesadministered on one day or two consecutive days, preferably on twoconsecutive days.

“Bisphosphonic acids and pharmaceutically acceptable salts thereof” aspharmaceutical agents are described for example in U.S. Pat. Nos.4,509,612; 4,666,895; 4,719,203; 4,777,163; 5,002,937 and 4,971,958 andin European Patent Applications Nos. 252,504 and 252,505, hereinincorporated by reference for such description.

Methods for the preparation of bisphosphonic acids and pharmaceuticallyacceptable salts thereof may be found in, e.g., U.S. Pat. Nos.3,962,432; 4,054,598; 4,267,108; 4,327,039; 4,407,761; 4,621,077;4,624,947; 4,746,654; 4,970,335; 5,019,651; 4,761,406; 4,876,248; in J.Org. Chem. 32, 4111 (1967) and European Patent Application 252,504,herein incorporated by reference. The pharmaceutically acceptable saltsof bisphosphonic acids may also be employed in the instant invention.Examples of base salts of bisphosphonic acids include ammonium salts,alkali metal salts such as potassium and sodium (including mono, di- andtri-sodium) salts (which are preferred), alkaline earth metal salts suchas calcium and magnesium salts, salts with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such as arginine, lysine, and so forth. Non-toxic, physiologicallyacceptable salts are preferred. The salts may be prepared by methodsknown in the art, such as described in European Patent Application252,504 or in U.S. Pat. No. 4,922,077, incorporated herein by reference.

In this invention, the medicament comprises 100 to 150 mg of aibandronic acid or a pharmaceutically acceptable salt thereof. Thepharmaceutical composition comprises at least 150% of a bisphosphonicacid or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients thereof. In one embodiment, thebisphosphonic acid is ibandronic acid. Preferably, the medicament isadministered as a single dose.

In a preferred embodiment of the present invention, the term“bisphosphonate” of the present invention corresponds to compounds ofgeneral formula

wherein A and X are independently selected from the group consisting ofhydrogen, hydroxy, halogen, amino, SH, phenyl, alkyl, mono- ordialkylamino, mono- or dialkylaminoalkyl, alkoxy, thioalkyl, thiophenyl,and aryl or heteroaryl moieties selected from the group consisting ofphenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl, and benzyl, whereinthe aryl or heteroaryl moiety is optionally substituted with alkyl.

In the foregoing chemical formula, A can include X, and X include A suchthat the two moieties can form part of the same cyclic structure.

The foregoing chemical formula is also intended to encompasscarbocyclic, aromatic and heteroaromatic structures for the A and/or Xsubstituents, e.g. naphthyl, quinolyl, isoquinolyl, adamantyl, andchlorophenylthio.

Preferred structures are those in which A is selected from the groupconsisting of hydrogen, hydroxy, and halogen, an X is selected from thegroup consisting of alkyl, halogen, thiophenyl, thioalkyl anddialkylaminoalkyl.

More preferred structures are those in which A is selected from thegroup consisting of hydrogen, hydroxy, and Cl and X is selected from thegroup consisting of alkyl, Cl, chlorophenylthio and dialkylaminoalkyl.

The preferred bisphosphonic acid or pharmaceutically acceptable salt isselected from the group consisting of alendronate, cimadronate,clodronate, tiludronate, etidronate, ibandronate, incadronate,minodronate, neridronate, olpadronate, risedronate, pamidronate,piridronate, zolendronate, EB-1053 or acceptable salts thereof, e.g.,ibandronic acid, monosodium salt, monohydrate.

Ibandronic acid(1-hydroxy-3-(N-methyl-N-pentyl)aminopropylidene-1,1-bisphosphonic acid)or physiologically compatible salts thereof are particularly preferred,e.g., ibandronic acid, monosodium salt, monohydrate.

The bisphosphonates and pharmaceutically acceptable salts may beadministered alone or in combination with other bone active drugs,either in fixed combinations or separately both physically and in time,including hormones, such as a steroid hormone, e.g., an estrogen; apartial estrogen agonist, or estrogen-gestagen combination; a calcitoninor analogue or derivative thereof, e.g., salmon, eel or human calcitoninparathyroid hormone or analogues thereof, e.g., PTH (1-84), PTH (1-34),PTH (1-36), PTH (1-38), PTH (1-31) or PPTS 893; a SERM (SelectiveEstrogen Receptor Modulator), e.g., raloxifene, lasofoxifene, TSE-434,FC1271, tibolone, vitamin D or an analog. Such additional bone activedrugs may be administered more frequently than the bisphosphonate.

Appropriate pharmaceutical compositions are known in the art and havebeen described e.g., in U.S. Pat. Nos. 6,143,326 and 6,294,196, hereinincorporated by reference.

For the preparation of tablets, coated tablets, drageés or hard gelatinecapsules, the compounds of the present invention may be admixed withpharmaceutically inert, inorganic or organic excipients. Examples ofsuitable excipients for tablets, drageés or hard gelatine capsulesinclude lactose, maize starch or derivatives thereof, talc or stearicacid or salts thereof.

The pharmaceutical compositions may also contain preserving agents,solubilizing agents, stabilizing agents, wetting agents, emulsifiers,sweeteners, colorants, odorants, salts for the variation of osmoticpressure, buffers, coating agents or antioxidants. They may also containother therapeutically valuable agents. Preferably, the pharmaceuticalcomposition is a film coated tablet wherein the tablet core comprises 50to 200 mg of a bisphosphonic acid or a pharmaceutically acceptable saltthereof as defined above and one or more pharmaceutically acceptableexcipients selected from the group consisting of lactose,polyvinylpyrrolidone, microcrystalline cellulose, crospovidone, stearicacid, silicon dioxide and the tablet core comprises one or morepharmaceutically acceptable excipients selected from the groupconsisting of hydroxypropyl methylcellulose, titanium dioxide, talc andpolyethylene glycol 6000. These compositions are known in the art anddescribed for example in U.S. Pat. Nos. 6,143,326 and 6,294,196.

Another aspect of the present invention is a method for treating,reducing or preventing disorders characterized by pathologicallyincreased bone resorption comprising to a mammal administration of aneffective amount of bisphosphonic acids or acceptable salts thereof. Inparticular, the invention refers to a method for treating, reducing orpreventing disorders characterized by pathologically increased boneresorption comprising oral administration of an effective amount of abisphosphonic acid or a pharmaceutically acceptable salt thereof,wherein approximately 50 to 250 mg bisphosphonic acid or apharmaceutically acceptable salt thereof are administered on one, two orthree consecutive days per month. As noted above, the effective amountof bisphosphonic acid or pharmaceutically acceptable salt thereof may beadministered as a single dose or as multiple sub-doses.

Preferably, in the method comprises administration of about 50 to 250mg, preferably about 100 to 150 mg, of a bisphosphonate or apharmaceutically acceptable salt thereof on one, two or threeconsecutive days per month. While the method includes administration ofthe dose through multiple sub-dosing, the preferred method provides asingle dose. Examples for administration of the dose through multiplesub-dosing are as follows, if the efficacious dose is 150 mg, the dosemay be two (2) 75 mg sub-doses administered on one day or on twoconsecutive days, or three (3) 50 mg sub-doses administered on one dayor on two or three consecutive days; if the efficacious dose is 100 mg,the dose may be two (2) 50 mg sub-doses administered on one day or twoconsecutive days, preferably on two consecutive days. The preferredbisphosphonate is ibandronate or a pharmaceutically acceptable saltthereof, e.g., ibandronic acid, monosodium salt, monohydrate.

Preferably, in the method according to the present invention, thebisphosphonic acid is selected from the group consisting of alendronate,cimadronate, clodronate, tiludronate, etidronate, ibandronate,incadronate, minodronate, neridronate, olpadronate, risedronate,pamidronate, piridronate, zolendronate, EB-1053 or pharmaceuticalacceptable salts thereof. More preferably, the bisphosphonic acid isibandronate or a pharmaceutically acceptable salt thereof, e.g.ibandronic acid, monosodium salt, monohydrate.

The invention will now be explained with reference to exemplifiedembodiments.

EXAMPLES Example 1 Pharmaceutical Composition

The Example shows the composition of a 50 mg tablet. The composition andpreparation of these tablets is known in the art and described forexample in U.S. Pat. Nos. 6,143,326 and 6,294,196.

Other compositions may be prepared by adjusting the ingredientsaccording to the amount of bisphosphonate, e.g. ibandronic acid,monosodium salt, monohydrate.

50 mg film-coated tablet Components mg per tablet Tablet core:Ibandronic acid, monosodium salt, monohydrate 56.250 Lactose monohydrate92.750 Povidone K 25 5.000 Microcrystalline cellulose 30.000Crospovidone 10.000 Purified stearic acid 4.000 Colloidal silicondioxide 2.000 Tablet coat: Hydroxypropyl methylcellulose 5.1425 Titaniumdioxide 2.4650 Talc 0.8925 Polyethylene glycol 6,000 1.5000 Finalweight: 210.000

1. A method for treating or inhibiting osteoporosis comprisingcommencing treatment by orally administering to a subject in need ofsuch treatment, a first dose, on a single day, of a pharmaceuticalcomposition comprising from about 100 mg to about 150 mg ofbisphosphonic acid or an amount of a pharmaceutically acceptable saltthereof that is equivalent to about 100 mg to about 150 mg of saidbisphosphonic acid and continuing said treatment by orallyadministering, once monthly on a single day, a pharmaceuticalcomposition comprising from about 100 mg to about 150 mg ofbisphosphonic acid or an amount of a pharmaceutically acceptable saltthereof that is eguivalent to from about 100 mg to about 150 mg ofbisphosphonic acid.
 2. The method according to claim 1, wherein thepharmaceutical composition comprises about 100 mg of bisphosphonic acidor an amount of a pharmaceutically acceptable salt thereof that isequivalent to about 100 mg of bisphosphonic acid.
 3. The methodaccording to claim 1, wherein the pharmaceutical composition comprisesabout 150 mg of bisphosphonic acid or an amount of a pharmaceuticallyacceptable salt thereof that is equivalent to about 150 mg ofbisphosphonic acid.
 4. The method of claim 1, wherein the pharmaceuticalcomposition comprises 100 mg of bisphosphonic acid or an amount of apharmaceutically acceptable salt thereof that is equivalent to 100 mg ofbisphosphonic acid.
 5. The method of claim 1 wherein the pharmaceuticalcomposition comprises 150 mg of bisphosphonic acid or an amount of apharmaceutically acceptable salt thereof that is equivalent to 150 mg ofbisphosphonic acid.
 6. The method of claim 1 wherein said bisphosphonicacid is risedronic acid or a pharmaceutically acceptable salt thereof.7. The method of claim 2 wherein said bisphosphonic acid is risedronicacid or a pharmaceutically acceptable salt thereof.
 8. The method ofclaim 3 wherein said bisphosphonic acid is risedronic acid or apharmaceutically acceptable salt thereof.
 9. The method of claim 5wherein said bisphosphonic acid is risedronic acid or a pharmaceuticallyacceptable salt thereof.
 10. The method of claim 1 wherein saidpharmaceutical composition is a solid pharmaceutical composition. 11.The method of claim 3 wherein said pharmaceutical composition is a solidpharmaceutical composition.
 12. The method of claim 5 wherein saidpharmaceutical composition is a solid pharmaceutical composition. 13.The method of claim 6 wherein said pharmaceutical composition is a solidpharmaceutical composition.
 14. The method of claim 8 wherein saidpharmaceutical composition is a solid pharmaceutical composition. 15.The method of claim 9 wherein said pharmaceutical composition is a solidpharmaceutical composition.
 16. A method for treating or inhibitingosteoporosis consisting of orally administering to a subject in need ofsuch treatment, once monthly, a pharmaceutical composition comprisingfrom about 100 mg to about 150 mg of bisphosphonic acid or an amount ofa pharmaceutically acceptable salt thereof that is equivalent to about100mg to about 150mg of said bisphosphonic acid.
 17. The methodaccording to claim 16, wherein the pharmaceutical composition comprisesabout 100 mg of bisphosphonic acid or an amount of a pharmaceuticallyacceptable salt thereof that is equivalent to about 100 mg ofbisphosphonic acid.
 18. The method according to claim 16, wherein thepharmaceutical composition comprises about 150 mg of bisphosphonic acidor an amount of a pharmaceutically acceptable salt thereof that isequivalent to about 150 mg of bisphosphonic acid.
 19. The method ofclaim 16 wherein the pharmaceutical composition comprises 100 mg ofbisphosphonic acid or an amount of a pharmaceutically acceptable saltthereof that is equivalent to 100 mg of bisphosphonic acid.
 20. Themethod of claim 16 wherein the pharmaceutical composition comprises 150mg of bisphosphonic acid or an amount of a pharmaceutically acceptablesalt thereof that is equivalent to 150 mg of bisphosphonic acid.
 21. Themethod of claim 16 wherein said bisphosphonic acid is risedronic acid ora pharmaceutically acceptable salt thereof.
 22. The method of claim 17wherein said bisphosphonic acid is risedronic acid or a pharmaceuticallyacceptable salt thereof.
 23. The method of claim 18 wherein saidbisphosphonic acid is risedronic acid or a pharmaceutically acceptablesalt thereof.
 24. The method of claim 20 wherein said bisphosphonic acidis risedronic acid or a pharmaceutically acceptable salt thereof. 25.The method of claim 16 wherein said pharmaceutical composition is asolid pharmaceutical composition.
 26. The method of claim 18 whereinsaid pharmaceutical composition is a solid pharmaceutical composition.27. The method of claim 20 wherein said pharmaceutical composition is asolid pharmaceutical composition.
 28. The method of claim 16 whereinsaid pharmaceutical composition is a solid pharmaceutical composition.29. The method of claim 18 wherein said pharmaceutical composition is asolid pharmaceutical composition.
 30. The method of claim 20 whereinsaid pharmaceutical composition is a solid pharmaceutical composition.once monthly on a single day, a pharmaceutical composition comprisingfrom about 100 mg to about 150 mg of bisphosphonic acid acceptable saltthereof that is eguivalent to from about 100 mg to about 150 mg ofbisphosphonic acid.